We evaluated the safety and efficacy of multiple repeat exposures to the next generation adenoviral vectors delivered to the lung by aerosolization to confirm the viability of this method as a gene therapy approach for patients with cystic fibrosis. Initially the exposure was to conscious macaque monkeys to closely mimic the situation in patient administration. This approach targets all airway epithelial cells, as the optimal airway epithelial cell target for gene therapy for cystic fibrosis has not yet been defined. Data obtained from this study could be submitted to regulatory agencies for assessment of this approach as therapy for cystic fibrosis patients. Many investigators have demonstrated that repeated administrations of adenovirus vector elicits a host immune response which includes production of neutralizing antibodies. The presence of these neutralizing antibodies markedly reduces the efficacy of repeated vector administrations. This two potential issues must be resolved prior to development of an effective therapeutic for humans. The vector should direct transgene expression that is maximally persistent and not result in a limiting antibody response or such response must b minimized. Recently we developed adenoviral vectors that resulted in more persistent transgene expression in mice. We then tested this vector in nonhuman primates. The results in the monkeys were not as predicted by the studies in mice. It is unclear whether this loss in transgene expression is associated with the expression cassette or the result in an immune response. Immunosuppression prior to and after adenoviral administration may reduce the levels of neutralizing antibodies such that effective re-administration may be achieved. Two approaches will be tested to reduce the immune response. The first will involve an immunosuppression regimes of cyclosporin in combination with a steroid and the second will examine a more novel immunomodulatory approach of blocking the co-stimulatory signal elicited by the interaction between the CD40 ligand (CD4OL) and CD40 using a "primatized" antibody against CD4OL.